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PE R SP EC TI V ES O N P SY CH O L O G I CA L S CIE N CE
Schizophrenia
Elaine Walker and Kevin Tessner
Emory University
ABSTRACT—Theoretical
conceptualizations of schizophrenia have undergone significant change in the past century.
Through the application of behavioral science methodology, psychologists have played a major role in the pivotal
scientific advances that have led us to contemporary
models. The field has moved from simplistic conceptualizations of mind–brain distinctions to models that encompass complex gene–environment interactions and neural
pathways that mediate the relation between psychosocial
events and brain dysfunction.
In this article, we address a challenging behavioral phenomenon
with a fascinating scientific history: schizophrenia. By definition,
schizophrenia is a psychotic disorder and is arguably the most
debilitating one (Walker, Kestler, Bollini, & Hochman, 2004).
Psychotic symptoms entail a distortion in the apprehension of
reality that is so severe it compromises the person’s ability to
function. Patients with schizophrenia show poorer courses than
patients with other psychotic and nonpsychotic disorders
(Harrow, Grossman, Jobe, & Herbener, 2005). Moreover, the
illness is typically chronic, and the modal age at onset is in late
adolescence or early adulthood—a period when most individuals are achieving autonomy (Jobe & Harrow, 2005). Yet there is
also considerable variability in the course of the illness. Harrow
and colleagues (2005) followed a group of patients diagnosed
with schizophrenia for over 15 years and found that approximately 40% of them had one or more periods of intermittent
recovery.
The primary domains of psychotic symptoms are perceptual,
ideational, and behavioral (Walker et al., 2004). In the perceptual domain, the key symptom is hallucinations: sensory
experiences in the absence of any sensory stimulus. The ideational manifestations are thought disorder and delusions. Behavioral abnormalities include bizarre movements, postures,
and rituals. In addition, many patients show affective abnormalities, such as blunted or inappropriate emotional expression.
The study of schizophrenia has a fascinating history characterized by major paradigm shifts. Although evidence suggesting
Address correspondence to Elaine Walker, Department of Psychology, Emory University, 532 North Kilgo Circle, Atlanta, GA 30322;
e-mail: [email protected].
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brain abnormality in schizophrenia was revealed in postmortem
and pneumoencephalographic studies conducted as early as the
late 1800s (see Torrey, 2002, for a review), these findings did not
have a significant impact on theorizing about schizophrenia. It
was not until the latter half of the 20th century that researchers
had relatively noninvasive scientific tools for studying brain
structure or function in vivo. Consequently, in the first half of the
20th century, the literature on psychotic disorders was dominated by a brain-versus-mind distinction that fueled many futile
debates about whether schizophrenia was a biological or a
psychological disorder. In fact, prior to the 1970s, the field of
psychiatry distinguished between organic and functional disorders, with the implicit assumption that only the former were
disorders of the brain (Heath, 1952). The psychoses, including
schizophrenia, were viewed as functional disorders. If a biological basis (e.g., brain injury or drugs) was suspected, the
patient’s psychosis was not diagnosed as schizophrenia. This
dichotomy presented significant challenges to the field of psychiatry by implying that psychiatry was a medical specialty that
dealt with nonmedical conditions (Heath, 1952). But gradually,
over the past half century, the functional–organic distinction has
been abandoned, giving way to the idea that schizophrenia is a
brain disorder. Moreover, decades of research have revealed that
schizophrenia is a brain disorder with complex and varied etiologies. This conclusion is a consequence of important scientific
developments in which psychologists have played a major role.
There is no disputing the fact that psychologists have been
instrumental in moving schizophrenia research through a series
of paradigm shifts moving toward a more accurate, albeit more
complex, picture of etiology. These shifts are, in part, a reflection
of changes in the prevailing theoretical trends in behavioral
science. Thus, theories about the nature and origins of psychosis
have changed in tandem with developments in our scientific
assumptions about the determinants of behavior.
This article examines some important turning points in our
scientific understanding of schizophrenia and the contributions
that psychologists have made at each juncture. First, there was a
shift from conceptualizations of schizophrenia as a disorder of
the mind, with primarily psychosocial causes, to the widespread
acceptance of the notion that brain abnormalities were involved.
A second shift, which overlapped the first, was the transition to
theories that encompassed genetic as well as environmental
factors. This shift set the stage for the emergence of diathesis-
Copyright r 2008 Association for Psychological Science
Volume 3—Number 1
Elaine Walker and Kevin Tessner
stress models of etiology. A third watershed involved broadening
the conceptualization of environmental factors to encompass
both psychosocial factors and bioenvironmental factors that
affect brain development. Finally, the field has recently witnessed a revision in our understanding of the way genetic influences are implicated. Rather than viewing genetics as a
blueprint that inevitably translates into behavior, we now recognize that the expression of the genotype is dependent on
bioenvironmental triggers. As described later in this article,
psychologists have played a major role in all of these critical
phases. In fact, one could argue that they have led the way in
most of the substantive theoretical shifts in the field.
PSYCHOSOCIAL CONCEPTUALIZATIONS
The early history of ideas about the nature of psychosis is well
documented (see Mirsky & Duncan, 2005, for a historical
overview). Not more than three centuries ago, the dominant
assumption was that psychotic symptoms reflected demonic
possession. But by the 20th century, the mental health movement was firmly established in Western nations, and the clinical
characteristics of schizophrenia were articulated by Emil
Kraepelin and Eugen Bleuler.
The recognition of psychotic disorders as mental illness set
the stage for a new debate that mirrored the ongoing dilemma
about the relation between mind and brain (Miller, 2005) and
reflected the distinction described earlier between functional
and organic disorders. Some people argued that psychosis was
the product of disordered mental processes that arose in response to adverse psychosocial factors, whereas others took the
position that impaired brain function was the critical and final
pathway. Those who focused exclusively on psychosocial determinants implicitly conceived of a disembodied mind by either ignoring or actively resisting notions of brain dysfunction.
Despite early speculations about brain dysfunction in psychosis, biological factors did not figure prominently in the
psychological theories of the late 1800s and early 1900s. For
example, most early psychodynamic theorists believed that
schizophrenia arose from a disturbance in the early formation of
object relations, or attachments to others (Arlow & Brenner,
1969; Freud, 1920). Freud proposed that psychosocial trauma
could disturb personality formation and bring about a mental
state of object fragmentation. Psychodynamic theorizing focused
on intrapsychic motives and posited that psychosis is attributable to ego weakness and that psychotic symptoms are symbolic
representations of repressed unconscious conflicts. Another
psychosocial perspective, the double-bind theory, posited that
psychotic symptoms emerge when a developing child is unable
to respond adequately to repeated conflicting injunctions (i.e.,
double-bind communications) from family members (Bateson,
Jackson, Haley, & Weakland, 1956). But the weight of empirical
research did not support either the psychodynamic or doublebind theories.
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A more fruitful psychosocial perspective focused on the
affective component of family communication and its role in
precipitating or exacerbating psychosis (Singer & Wynne, 1963;
Vaughn & Leff, 1976). The phrase expressed emotion came to
refer to communication with the patient that is critical, hostile,
or emotionally overinvolved. Studies revealed that high levels of
expressed emotion were associated with greater risk of relapse
(Vaughn & Leff, 1976), suggesting a role for psychosocial factors
in the recurrence of psychotic episodes. Other researchers,
however, raised questions about the nature of the causal relationship. Do family members’ negative communications contribute to relapse, or are family members reacting to the patient’s
impending relapse, or both? Psychologists have demonstrated
that the causal relation between expressed emotion and relapse
is bidirectional, but that negative expressed emotion can indeed
contribute to patient relapse (Goldstein, 1987; King, Ricard,
Rochon, Steiger, & Nelis, 2003). So the psychosocial environment does matter, but in a different way than was originally
assumed. As described later, contemporary views of this process
include neural mechanisms that can translate stress into brain
dysfunction (Walker & Diforio, 1997).
MIND VERSUS BRAIN: THE CONTRIBUTION
OF NEUROPSYCHOLOGY
Although the notion that psychotic disorders reflect brain dysfunction was overshadowed by psychosocial theories in the early
1900s, this idea is not unique to 20th-century thinkers. More
than 1,000 years ago, Greek and Roman physicians viewed
madness as a disease of the brain (see Mirsky & Duncan, 2005,
for a review). Ancient Greek and Roman medical writers described internal and external factors that produced an imbalance of bile and phlegm, which led to distinguishable behavioral
disturbances. Much later, in A Treatise on Madness, Battie (1758)
described madness as a disorder that could have physical
(possibly hereditary) as well as environmental causes. He observed that madness was frequently viewed as a single disorder,
but ‘‘when thoroughly examined, it discovers as much variety
with respect to its causes and circumstances as any distemper
whatever’’ (Battie, 1758, p. 94). For example, one cause of
madness that Battie suggested was pressure on a portion of the
brainstem, in particular, the medulla. But the scientific techniques for documenting brain dysfunction were not available to
Battie and his predecessors, so their speculations did not garner
much attention.
Then the tide turned in the 1960s, and systematic research
began to yield evidence that raised questions about the primacy
of psychosocial determinants and the nonorganic nature of
schizophrenia. During this era, the major line of empirical investigation that pointed to brain dysfunction was neuropsychological research (see Levin, Yurgelun-Todd, & Craft, 1989, for a
review). Among the many psychologists who led the way were
Allan Mirsky and Robert Heaton.
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Schizophrenia
The field of neuropsychology grew out of the use of psychological test batteries administered to war veterans who had
suffered head injuries in combat. Systematic comparisons of the
cognitive performance of patients with lesions in various brain
regions revealed that damage to specific areas was associated
with characteristic deficits on cognitive tasks.
In 1969, Mirsky published a seminal paper entitled Neuropsychological Bases of Schizophrenia. On the basis of accumulating neuropsychological data, he proposed what may have
been the first neural circuitry model of brain dysfunction in
schizophrenia. A subsequent wave of neuropsychological
studies revealed that patients with schizophrenia manifested a
performance pattern similar to those of certain brain-damaged
patients, leading Robert Heaton and his colleagues (Heaton,
Baade, & Johnson, 1978) to conclude that patients with
schizophrenia were suffering from frontal- or temporal-lobe
brain damage. The power of neuropsychological techniques was
documented in a recent meta-analysis showing that neuropsychological measures were more effective than most biological
measures—including neuroimaging—in differentiating schizophrenia patients from healthy controls (Heinrichs, 2004).
Thus, even before the advent of neuroimaging technology in
the form of computerized tomography (Weinberger, Torrey, Neophytides, & Wyatt, 1979), many psychologists believed that
schizophrenia involved brain dysfunction. Neuropsychology
provided nontechnical but reliable tools for measuring the integrity of brain function and yielded findings that have now been
confirmed and extended by hundreds of neuroimaging studies.
For example, imaging studies have shown that hypofrontality—
reduced blood flow in the frontal lobe—is correlated with performance deficits on neuropsychological measures of frontallobe function (Davidson & Heinrichs, 2003).
GENETICS OF SCHIZOPHRENIA: THE FIRST PHASE
Overlapping the growing trend toward localizing vulnerability
for psychotic disorders in the brain, other investigators were
zeroing in on etiologic factors. Paul Meehl was among the many
pioneering psychologists in the field of schizophrenia. In 1962,
Meehl published a classic paper entitled Schizotaxia, Schizotypy, Schizophrenia, in which he proposed a biological predisposition to schizophrenia that he referred to as schizotaxia, a
genetic defect in neurointegration. He conjectured that
schizotaxia does not always lead to schizophrenia and that it has
a higher base rate than the population prevalence rate of 1% for
schizophrenia. In a highly favorable environment, schizotaxia is
not associated with an observable behavioral syndrome. Meehl
argued, however, that many schizotaxic individuals develop a
syndrome known as schizotypy—which involves perceptual
abnormalities and cognitive deficits—and that only a minority
would develop schizophrenia. In summary, without the benefit of
much empirical data, Meehl presaged several key scientific
advances in the field. Most notably, he posited that genetic and
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environmental factors interact in the etiology of schizophrenia
and that some vulnerable individuals manifest subclinical signs
of psychosis.
Within the same decade, findings from behavioral genetic
studies of mental disorders began to accumulate, and they
confirmed Meehl’s ideas. Three methods dominated this line of
investigation (see Gottesman, 1991, for a detailed review of
these methods and the research findings). First, the family history method examined the occurrence of schizophrenia and
other psychoses in patients’ biological relatives. The findings
showed that the rate of disorder in relatives varied as a function
of genetic similarity: First-degree relatives were more likely to
be affected than second-degree relatives who, in turn, had
higher rates of disorder than the general population.
A second and more powerful method for studying genetic
influences on mental disorders is the twin method. Because
monozygotic (MZ) twins are the product of one zygote that splits
after fertilization, the two members of the twin pair have identical genotypes. (Technically, due to postcleavage mutations, the
genotypes can be nonidentical.) In contrast, dizygotic (DZ) or
fraternal twins share, on average, 50% of their genes. Numerous
twin studies have been published, and the results consistently
show a higher rate of concordance for schizophrenia in MZ twins
than in DZ twins. Lending additional support to the role of genetic factors in the etiology of schizophrenia, adoption studies
have shown that the biological offspring of mothers with
schizophrenia who are reared in adoptive homes from infancy
have a higher rate of schizophrenia than do adoptees with
healthy biological parents.
Among the major figures spearheading the application of
behavioral genetic approaches to schizophrenia were psychologists Irving Gottesman (Gottesman & Shields, 1966) and Philip
Holzman (1977). Gottesman conducted seminal behavioral genetic studies and was among the first to argue for a polygenic
mode of transmission for vulnerability to schizophrenia—in
other words, that multiple genes are implicated (Gottesman,
1991). A competing model assumed a single major locus, and
Holzman was a leading proponent of this position (Holzman,
1977). Ultimately the research results did not support a single
major-locus model. By the early 1980s, most people rejected the
idea of a single, culpable gene, and the polygenetic model of
multiple risk genes acting in concert gained dominance (Faraone & Tsuang, 1985).
Taken together, evidence from behavioral genetics paradigms
points to a genetic basis for at least some cases of schizophrenia.
But critical questions remain: If there is a genetic predisposition, is it always expressed in behavior, and does it inevitably
lead to illness? As Meehl suggested in 1962, the answer to the
latter question is ‘‘no,’’ given that the concordance rate for MZ
twins is 50% or lower. But the absence of clinical illness does
not necessarily preclude behavioral abnormalities. Behavioral
genetics research has shown that the biological relatives of
people with schizophrenia often manifest signs of schizotypy, as
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Elaine Walker and Kevin Tessner
described by Meehl. These signs include subclinical manifestations of psychotic symptoms—such as magical thinking,
suspiciousness, and odd beliefs—as well as impairment in
cognitive, affective, and social functioning.
Philip Holzman studied the biological relatives of patients
and identified several biobehavioral measures that reflected a
genetic predisposition for schizophrenia. Holzman referred to
these markers as endophenotypes for the illness (Gottesman &
Gould, 2003). For example, Holzman’s studies of patients’ relatives revealed abnormalities in visual tracking similar to abnormalities observed in patients with schizophrenia (Holzman,
1977).
Molecular genetics research has recently shed light on the
mechanisms that might modulate gene expression. Gottesman
and his colleagues have shown that there are differences between members of discordant MZ-twin pairs in the expression of
genes due to DNA methylation (Petronis et al., 2003). Their
study examined DNA methylation in the dopamine D2-receptor
gene and revealed that affected twins from the discordant MZ
pairs had methylation patterns more similar to the affected twins
in concordant pairs than to their unaffected co-twins. These
findings not only highlight the differences between co-twins in
MZ-twin pairs, but they also demonstrate that stochastic events
and the environment influence the regulation of gene activity.
EMERGENCE OF THE DIATHESIS-STRESS MODEL
Findings from behavioral genetics research served as the impetus for the diathesis-stress model. In this framework, diathesis
refers to a constitutional vulnerability, and stress refers to adverse events that impinge on the vulnerable individual. In the
1960s and 1970s, the diathesis was typically assumed to be
genetically determined, and stress stemmed from childhood
psychosocial events. Joseph Zubin and Bonnie Spring (Zubin &
Spring, 1977) were among the most influential diathesis-stress
theorists. They assumed that individuals inherited a diathesis
that was expressed behaviorally only when psychosocial
stressors exceeded the individual’s capacity to cope.
Adoption studies have yielded support for the diathesis-stress
model. For example, Tienari et al. (1987) examined the diagnostic outcome for the biological offspring of parents with
schizophrenia and found that the quality of the rearing environment was a significant determinant of psychiatric outcome;
the incidence of schizophrenia was much higher in individuals
reared in a disturbed adoptive families. Similarly, in a study of
nonadopted offspring of patients with schizophrenia, Walker,
Downey, and Bergman (1989) found that individuals exposed to
maltreatment were more likely to develop behavioral problems.
These and other findings provide an empirical foundation for the
diathesis-stress model. Thus, the model’s basic assumption—
that schizophrenia is the product of an interaction between
constitutional vulnerability and environmental factors—continues to dominate theories of etiology.
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In recent decades, however, the breadth and complexity of
etiological models has changed dramatically. In particular,
scientific findings that emerged in the 1970s led researchers to
broaden their conceptualization of environmental factors. Thus,
in addition to focusing on psychosocial stressors, such as disturbed family environments, researchers began to investigate
biological stressors as well.
The Broadened Scope of Environmental Influences:
Bioenvironmental Factors
Early diathesis-stress models assumed that psychosocial stress
and genetics acted unidirectionally and through nonmediated
pathways to determine illness. Until the 1970s, researchers did
not generally consider that stress might encompass biological
factors, that stress could occur during fetal development, or that
psychosocial effects were mediated by neural processes.
As empirical data have accumulated, however, it is increasingly apparent that bioenvironmental insults to the brain must
be considered among the environmental factors that contribute
to schizophrenia. As early as the 1970s, Sarnoff Mednick, a
psychologist and pioneer in schizophrenia research, alerted the
scientific community to the role of prenatal factors in the etiology of schizophrenia (Mednick, Mura, Schulsinger, & Mednick, 1971). Mednick later uncovered the link between maternal
influenza infection and schizophrenia, and he was the first to
suggest the hippocampus as a brain region vulnerable to prenatal complications in schizophrenia (Lyon, Barr, Cannon,
Mednick, & Shore, 1989; Mednick, Machon, Huttunen, &
Bonett, 1988). Numerous studies have subsequently confirmed
the association of prenatal and delivery complications with
schizophrenia and other psychoses (Kunugi, Nanko, & Murray,
2001). This work not only broadened our understanding of environmental effects, it also showed that these effects could be
traced to the fetal period and could result in compromised fetal
neurodevelopment.
The range of potential prenatal insults was further extended
by evidence that psychosocial events could also compromise
fetal development. In 1978, Huttunen and Niskanen published
an important study showing that women who were exposed to
psychosocial stress during pregnancy were more likely to give
birth to a child who later developed mental illness, such as
schizophrenia. At the time this study was published, relatively
little was known about the biological processes that could mediate a relation between prenatal maternal stress and the mental
health of offspring. But subsequent research with animals has
shed important light on these mechanisms by demonstrating that
elevated maternal stress hormones (i.e., glucocorticoids) can
adversely influence fetal neurodevelopment.
More recently, another bioenvironmental influence has been
discovered: Adolescent drug use, specifically marijuana, can
contribute to psychosis (Verdoux, Tournier, & Cougnard, 2005).
Evidence to support this relation has come from retrospective
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Schizophrenia
and prospective studies. Although the mechanisms involved are
not yet known, there is reason to suspect that the principal active
ingredient of cannabis, D-9-tetrahydrocannabinol (D-9-THC),
increases the risk for psychosis by augmenting dopamine neurotransmission and stress hormone release (D’Souza et al.,
2005; Viveros, Llorente, Moreno, & Marco, 2005).
evidence for fetal neurodevelopmental abnormalities in
schizophrenia, these findings suggest that both neurodevelopmental and neurodegenerative processes are implicated. So how
can these two processes be reconciled with our understanding of
genetic factors in schizophrenia?
THE SECOND GENETIC REVOLUTION IN
SCHIZOPHRENIA RESEARCH
Neurodevelopmental Perspectives
Evidence suggesting that abnormal fetal brain development can
contribute to the risk for schizophrenia converged with other
findings that behavioral signs of vulnerability can be present at
birth. For example, studies of the infant offspring of patients with
schizophrenia (Fish, 1977) and subsequent archival research
using home movies (Walker, 1994) revealed that subtle signs of
neuromotor and emotional dysfunction were apparent in patients with schizophrenia as early as infancy. These and related
reports launched a new conceptual debate. Some researchers
began to refer to schizophrenia as a neurodevelopmental disorder, arguing that the illness involves abnormalities in fetal
development of the central nervous system (Murray, O’Callaghan, Castle, & Lewis, 1992). Others juxtaposed this idea with
the notion that schizophrenia involves a degenerative brain
process that begins in young adulthood, when early clinical
signs are manifested (Delisi et al., 1997). A debate between
neurodevelopmental and degenerative models ensued.
In recent years, new findings on adolescent brain development have provided a basis for reconciling these two perspectives (Walker, 2002). One of the most well-established
observations of psychotic disorders is that their clinical onset
typically occurs in late adolescence or early adulthood. To be
consistent with the modal developmental course of the illness,
neurodevelopmental models must account for the dramatic rise
in onset during adolescence. Advances in noninvasive neuroimaging have made it possible for researchers to examine brain
development. Within the past decade, changes in brain structure and function throughout adolescence have been identified
(Walker, 2002). Furthermore, during adolescence, individuals at
risk for psychosis show a pattern of gray- and white-matter brain
changes that differs from that observed in controls. Healthy
adolescents lose gray matter at the rate of 1%–2% per year,
whereas adolescents with schizophrenia show a more rapid and
progressive loss of gray matter in frontal and temporal cortices
(roughly 3%–4% per year; Toga, Thompson, & Sowell, 2006).
The cellular mechanisms responsible for the loss of gray matter
are unknown, but they are thought to involve neurodegenerative
processes that include abnormal increases in apoptosis or
neuronal death (Perez-Neri, Ramirez-Bermudez, Montes, &
Rios, 2006).
Future research in the genetics of schizophrenia may provide
insight into the mechanisms underlying neuromaturational
changes during critical developmental periods and into the
degenerative processes leading to psychosis. Combined with the
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As reviewed earlier, the first phase of research on the genetics of
schizophrenia firmly established that vulnerability to schizophrenia could be inherited, and the data were most consistent
with the hypothesis that multiple genes act in concert (Gottesman, 1991). But, empirical findings that emerged in the 1970s
and 1980s made it increasingly apparent that the number of
relevant genes was larger than originally assumed.
In the 1990s, a plethora of new genetic methods, including
linkage and association studies, was applied to the study of
schizophrenia. But the enthusiasm that accompanied the introduction of these methods far exceeded their ability to shed
light on the genetics of schizophrenia. Each initially positive
finding on a specific gene or chromosome was followed by a
series of failures to replicate (Kirov, O’Donovan, & Owen, 2005).
When the technology for scanning the human genome was introduced, it yielded some significant findings, but replications
were uncommon. A meta-analysis of the results suggested evidence for linkage on at least 12 chromosomes, and many of these
had already been implicated in other psychiatric disorders
(Lewis et al., 2003). Although the absence of consistent genetic
findings has contributed to a pessimistic outlook among some
investigators, the results are, in fact, providing us with critical
information about the nature of schizophrenia.
Why has it been so difficult to elucidate the genetics of
schizophrenia and other forms of psychosis? There are several
likely reasons. First, it appears that schizophrenia is a complex
syndrome for which there are multiple contributing genes, each
with alleles (i.e., variant forms) that have relatively weak effects
on their own. Moreover, the relevant genes may produce more
than one biobehavioral effect, and they may interact with each
other (gene–gene interactions). Second, the behavioral syndrome (phenotype) we now label schizophrenia is heterogeneous;
its manifestations across patients are highly variable, and it is
likely that the genetic determinants also vary across cases.
Third, it appears that diagnostic boundaries in the current Diagnostic and Statistical Manual of Mental Disorders (DSM–IV;
American Psychiatric Association, 1994) do not distinguish on
the basis of etiology; many of the genes that have been associated with schizophrenia have also been shown to be associated
with other forms of psychosis (Craddock, O’Donovan, & Owen,
2005). So it appears that genetic susceptibility overlaps the
diagnostic boundaries that differentiate schizophrenia from
mood disorders with psychotic features. In addition, we have no
biological markers of psychosis to provide clues in the search for
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Elaine Walker and Kevin Tessner
candidate genes. Fourth, currently available genetic analyses
are somewhat ineffective at detecting weak effects of single
genes and are even less effective at detecting interactions among
genes. Finally, the strong evidence that both biological and
psychosocial aspects of the environment influence the expression of genetic vulnerability makes it difficult to identify the
genetic factors that confer vulnerability. Nonetheless, the
enormous body of literature on schizophrenia and other psychoses leads to the inescapable conclusion that they are complex diseases that arise from complex gene–environment
interactions.
Gene–Environment Interactions: The Real Nature of
Nature–Nurture Interactions
Diathesis-stress models of the etiology of schizophrenia were
fueled by the idea of nature–nurture interaction. But it is only
recently that scientific research on gene–environment interactions has yielded findings that have given tangible meaning to
the concept. Psychologists Avshalom Caspi and Terrie Moffit
have led the development of new research approaches to clarify
gene–environment interactions in the etiology of mental disorders (Moffitt, Caspi, & Rutter, 2005).
In a seminal study, Caspi et al. (2003) found that 33% of individuals with a specific allele of the serotonin transporter gene
became depressed in the presence of severe adverse life events,
whereas only 17% of the individuals without this genotype developed major depression. These findings have been replicated
by at least one other research group (Wilhelm et al., 2006). At
this point, the study of gene–environment interactions in the
etiology of psychosis is in its infancy, but there is reason to
believe that such interactions exist. As a prime example, in a
recent report, Caspi and colleagues found that a functional
polymorphism in the catechol-O-methyltransferase (COMT)
gene moderated the influence of adolescent cannabis use on risk
for adult psychosis. In a large population sample, carriers of the
COMT valine158 allele were most likely to exhibit psychotic
symptoms and to develop schizophreniform disorder if they used
cannabis. Cannabis had no adverse influence on individuals
with two copies of the methionine allele. These findings illustrate a Gene Environment interaction in the etiology of psychosis and suggest that several susceptibility genes for
psychosis influence vulnerability to bioenvironmental factors
(Caspi et al., 2005).
THE NEW CONCEPTUAL FRAMEWORK
We now have a conceptual model of schizophrenia and other
psychoses that is undoubtedly more complex than the models
envisioned by psychologists who first described the syndrome.
The functional versus organic distinction that dominated psychiatry into the 1960s has given way to contemporary models
that incorporate multiple levels of analysis. Psychologists have
facilitated these advances by applying the tools of behavioral
science. First, neuropsychologists moved the field forward by
establishing that people with schizophrenia manifest a pattern of
cognitive performance suggestive of brain dysfunction. One
source of this brain dysfunction, heredity, was demonstrated
through the application of behavioral genetics methods. Other
sources of constitutional vulnerability—in particular, prenatal
influences—were then identified, and the scope of etiologic
influences was expanded to include bioenvironmental factors.
More recently, psychologists have moved the field forward
through innovative studies that illustrate the importance of
gene–environment interactions. These scientific advances have
been paralleled by the emergence of more sophisticated models
of etiology that move far beyond the mind–brain dualism that
was evident in early functional–organic distinctions. Again,
psychologists have been in the forefront of developing these new
models. For example, Walker and Diforio (1997) proposed a
neural diathesis-stress model that encompasses genetic, bioenvironmental, and psychosocial factors (see Fig. 1). This model
assumes that constitutional vulnerability to psychotic disorders
is determined by genetic (inherited) and prenatal (acquired)
factors and that adult psychiatric outcome is determined by the
cumulative effects of exposure to environmental stressors that
act through the neural circuitry that subserve the biological
Fig. 1. A contemporary neural diathesis-stress model of the etiology of psychosis.
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Schizophrenia
stress response. The model also emphasizes the role of neuromaturational processes that unfold during adolescence. With
regard to the latter, it is assumed that hormonal changes during
adolescence can trigger the expression of liability genes and the
neural circuitry malfunction that underlie psychotic symptoms.
Along these same lines, Nuechterlein and Dawson (1984) have
presented a model that emphasizes the cumulative interactions
among biological and environmental vulnerability factors, as
well as the modulating effect of protective factors such as patients’ coping mechanisms.
THE NEXT FRONTIERS
Empirical research has shown that schizophrenia is not the
consequence of a single genetic or environmental factor. The
contemporary view is that schizophrenia is a heterogeneous
disorder and that its polygenic etiology overlaps with other
psychotic disorders. This view does not exclude the possibility
that psychosis is the product of a singular neuropathological
process—perhaps an abnormality in a specific neural circuit or
set of circuits.
Current approaches to the treatment of schizophrenia include
both psychotropic medications and psychotherapeutic techniques (Walker et. al., 2004). But antipsychotic medications are
considered the first line of intervention, and many patients do
not have access to other forms of treatment. Furthermore, although the newer atypical antipsychotics have fewer adverse
side effects than first-generation drugs, they control symptoms
rather than curing the disorder, and most patients face a lifetime
of disability. Major advances in treatment will undoubtedly
follow advances in our understanding of the neural mechanisms
that give rise to psychotic syndromes.
Future research on the etiology of schizophrenia will be
characterized by two major thrusts. First, there will be a more
intense focus on the developmental period immediately prior to
the clinical onset of the illness. The period of subclinical behavioral dysfunction that precedes the onset of schizophrenia
has been referred to as the prodrome. As mentioned, most individuals who develop the disease show prodromal signs during
adolescence. This well-documented fact is leading researchers
to intensify their efforts to chart postpubertal biological and
psychological changes. As yet, there is no better predictor of
impending psychosis than prodromal behavioral signs. It is
therefore likely that behavioral measures will be the primary
tool for identifying persons at highest risk, so psychologists will
play an even greater role.
Second, there will be intensified focus on studies of gene–
environment interactions with the aim of elucidating mechanisms through which genetic vulnerabilities are translated into
clinical disorder. Included in this will be the burgeoning field of
epigenetics, the study of changes in gene expression that occur
without a change in DNA sequence. Research has shown that
epigenetic mechanisms influence both the normal and abnormal
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(e.g., cancer, autoimmune diseases) development and survival of
cells and that they are altered by hormones, including stress
hormones.
Finally, it is likely that adolescence will prove to be a critical
period for preventive intervention for psychosis. Some psychologists have speculated that hormonally driven neuromaturational processes play a role in triggering the onset of the
prodrome in adolescence. Hormonal factors may, in fact, trigger
the expression of disease-related gene patterns. It is possible,
therefore, that preventive interventions will entail psychological
or pharmacological techniques that change the hormonal milieu
and thereby prevent aberrant brain changes that contribute to
psychosis.
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